Telemedicine and Epilepsy Care.

Telemedicine is a method of health care delivery well suited for epilepsy care, where there is an insufficient supply of trained specialists. The telemedicine "Hub and Spoke" approach allows patients to visit their local health clinic ('Spokes') to establish appropriate care and monitoring for their seizure disorder or epilepsy, and remotely connect with epileptologists or neurologists at centralized centers of expertise ('Hubs'). The COVID-19 pandemic resulted in an expansion of telemedicine capabilities and use, with favorable patient and provider experience and outcomes, allowing for its wide scale adoption beyond COVID-19.

Non-rapid eye movement sleep determines resilience to social stress.

Resilience, the ability to overcome stressful conditions, is found in most mammals and varies significantly among individuals. A lack of resilience can lead to the development of neuropsychiatric and sleep disorders, often within the same individual. Despite extensive research into the brain mechanisms causing maladaptive behavioral-responses to stress, it is not clear why some individuals exhibit resilience. To examine if sleep has a determinative role in maladaptive behavioral-response to social stress, we investigated individual variations in resilience using a social-defeat model for male mice. Our results reveal a direct, causal relationship between sleep amount and resilience-demonstrating that sleep increases after social-defeat stress only occur in resilient mice. Further, we found that within the prefrontal cortex, a regulator of maladaptive responses to stress, pre-existing differences in sleep regulation predict resilience. Overall, these results demonstrate that increased NREM sleep, mediated cortically, is an active response to social-defeat stress that plays a determinative role in promoting resilience. They also show that differences in resilience are strongly correlated with inter-individual variability in sleep regulation.

To many of us, it may seem obvious that sleep is restorative: we feel better after a good night's rest. However, exactly how sleep benefits the brain and body remains poorly understood. One clue may lie in neuropsychiatric disorders: these conditions ­ such as depression and anxiety ­ are often accompanied by disrupted sleep. Additionally, these neuropsychiatric disorders are frequently caused or worsened by stress, which can also interfere with sleep. This close association between stress and sleep has led some to hypothesize that sleep serves to overcome the adverse effects of stress on the brain, but this hypothesis remains largely untested. One type of stress that is common to all mammals is social stress, defined as stress caused by social interactions. This means that mice and other rodents can be subjected to social stress in the laboratory to test hypotheses about the effects of stress on the brain. Importantly, in both animals and humans, there are individual differences in resilience, or the ability to overcome the adverse effects of stress. Based on this information, Bush et al. set out to establish whether sleep can regulate resilience to social stress in mice. When the mice were gently kept awake during their normal sleep time, resilience decreased and so the mice were less able to overcome the negative effects of stress. Conversely, increasing sleep, by activating an area of the brain responsible for initiating sleep, increased the mice's resilience to social stress. Thus, Bush et al. showed that changes in sleep do lead to changes in resilience. To find out whether resilience can be predicted by changes in sleeping patterns, Bush et al. studied how both resilient mice and those susceptible to stress slept before and after social stress. Resilient mice would often sleep more after social stress; meanwhile, few changes were observed in susceptible mice. Surprisingly, sleep quality also predicted resilience, with resilient mice sleeping better than susceptible mice even before exposure to social stress. To determine whether the differences in sleep that predict resilience can be detected as brain activity, Bush et al. placed electrodes in two regions of the prefrontal cortex ­ a part of the brain important for decision-making and social behaviors ­ to measure how mice recovered lost sleep. This experiment revealed that the changes in sleep that predict resilience are prominent in the prefrontal cortex. Overall, Bush et al. reveal that sleeping more and sleeping better promote resilience to social stress. Furthermore, the results suggests that lack of sleep may lead to increased risk of stress-related psychiatric conditions. Humans are one of the few species that choose to deprive themselves of sleep: Bush, et al. provide evidence that this choice may have significant consequences on mental health. Furthermore, this work creates a new model that lays the groundwork for future studies investigating how sleep can overcome stress on the brain.

Bmal1 function in skeletal muscle regulates sleep.

Sleep loss can severely impair the ability to perform, yet the ability to recover from sleep loss is not well understood. Sleep regulatory processes are assumed to lie exclusively within the brain mainly due to the strong behavioral manifestations of sleep. Whole-body knockout of the circadian clock gene Bmal1 in mice affects several aspects of sleep, however, the cells/tissues responsible are unknown. We found that restoring Bmal1 expression in the brains of Bmal1-knockout mice did not rescue Bmal1-dependent sleep phenotypes. Surprisingly, most sleep-amount, but not sleep-timing, phenotypes could be reproduced or rescued by knocking out or restoring BMAL1 exclusively in skeletal muscle, respectively. We also found that overexpression of skeletal-muscle Bmal1 reduced the recovery response to sleep loss. Together, these findings demonstrate that Bmal1 expression in skeletal muscle is both necessary and sufficient to regulate total sleep amount and reveal that critical components of normal sleep regulation occur in muscle.

Maternal Ube3a Loss Disrupts Sleep Homeostasis But Leaves Circadian Rhythmicity Largely Intact.

Individuals with Angelman syndrome (AS) suffer sleep disturbances that severely impair quality of life. Whether these disturbances arise from sleep or circadian clock dysfunction is currently unknown. Here, we explored the mechanistic basis for these sleep disorders in a mouse model of Angelman syndrome (Ube3a(m-/p+) mice). Genetic deletion of the maternal Ube3a allele practically eliminates UBE3A protein from the brain of Ube3a(m-/p+) mice, because the paternal allele is epigenetically silenced in most neurons. However, we found that UBE3A protein was present in many neurons of the suprachiasmatic nucleus--the site of the mammalian circadian clock--indicating that Ube3a can be expressed from both parental alleles in this brain region in adult mice. We found that while Ube3a(m-/p+) mice maintained relatively normal circadian rhythms of behavior and light-resetting, these mice exhibited consolidated locomotor activity and skipped the timed rest period (siesta) present in wild-type (Ube3a(m+/p+)) mice. Electroencephalographic analysis revealed that alterations in sleep regulation were responsible for these overt changes in activity. Specifically, Ube3a(m-/p+) mice have a markedly reduced capacity to accumulate sleep pressure, both during their active period and in response to forced sleep deprivation. Thus, our data indicate that the siesta is governed by sleep pressure, and that Ube3a is an important regulator of sleep homeostasis. These preclinical findings suggest that therapeutic interventions that target mechanisms of sleep homeostasis may improve sleep quality in individuals with AS. SIGNIFICANCE STATEMENT: Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by loss of expression of the maternal copy of the UBE3A gene. Individuals with AS have severe sleep dysfunction that affects their cognition and presents challenges to their caregivers. Unfortunately, current treatment strategies have limited efficacy due to a poor understanding of the mechanisms underlying sleep disruptions in AS. Here we demonstrate that abnormal sleep patterns arise from a deficit in accumulation of sleep drive, uncovering the Ube3a gene as a novel genetic regulator of sleep homeostasis. Our findings encourage a re-evaluation of current treatment strategies for sleep dysfunction in AS, and suggest that interventions that promote increased sleep drive may alleviate sleep disturbances in individuals with AS.